The overall survival for patients diagnosed with advanced or metastatic cancers has changed little despite the development of novel targeted therapeutics. The basis of most cancer care remains cytotoxic therapy - radiation and chemotherapy - that kills rapidly proliferating cells. Current drug development continues to screen for agents under permissive growth conditions with readouts that are surrogates for proliferation. However, these strategies provide only incremental improvements as in vivo microenvironmental tumor conditions and the complex cellular involvement promote heterogeneity within the tumor through genetic and non-genetic variations associated with therapeutic resistance, angiogenesis, and tumor progression. Multiple approaches are under development to improve the identification of druggable targets within these critical tumor cell variants. We and others are investigating one source of tumor heterogeneity - the differentiation hierarchy incorporated within the cancer stem cell hypothesis. We believe that the cancer stem cell phenotype is plastic and defined by both cell autonomous and external cues so high throughput analyses, although reported, may not fully represent the cancer stem cell state. We have previously demonstrated that brain tumor stem cells are resistant to radiation and also promote tumor angiogenesis. Based on this background, we hypothesize that inhibiting key survival pathways active in brain tumor stem cells but not normal tissue stem cells will augment the efficacy of current brain tumor therapies. Specifically, we propose to: 1. Evaluate the anti-angiogenic capacity of a novel brain tumor stem cell targeting agent. 2. Determine the therapeutic efficacy of a novel brain tumor stem cell targeting agent in combination with bevacizumab. 3. Determine the therapeutic efficacy of a novel brain tumor stem cell targeting agent in combination with radiation and chemotherapy. We hope that these studies will lay the foundation for direct translation into therapeutic trials. PUBLIC HEALTH RELEVANCE: Glioblastomas are among the deadliest of all human cancers despite treatment with radiation, chemotherapy, and - most recently - drugs that block new blood vessel growth to feed tumors. Within glioblastomas, cells called cancer stem cells have been found that in laboratory studies are resistant to radiotherapy and chemotherapy and also stimulate new blood vessels to grow. We will test ways of attacking the cancer stem cells to sensitize them to the effects of current brain cancer treatments.